PROJECT SUMMARY/ABSTRACT The goal of this proposal is to assess the feasibility of a non-invasive nanoparticle platform for tool delivery to the brain. We propose to generate mixed-surface, cystamine core PAMAM dendrimers with unique features. By significantly expanding the cargo size, cell populations in the brain can be targeted genetically utilizing regulatory elements exceeding the size limit of current tools. In addition, increased cargo size will allow delivery of multiple smaller molecules at specific optimal ratios, an increasing need with newly developed multi- component systems. By improving biodistribution through modifying surface features of the nanoparticles, tool delivery to the brain can be accomplished evenly through peripheral non-invasive application. Goals will be achieved by pursuing two interrelated aims: 1) Developing dendrimers capable to complex large DNA constructs, up to 100 kb, by varying surface composition, dendrimer:DNA ratios, and dendrimer generation/size; 2) Developing dendrimers combining high DNA packaging capacity with excellent serum resistance, ability to cross the blood-brain-barrier, efficient cellular uptake as well as intracellular release of cargo by precisely tuning surface features. Our experiments are early stage, require proof of principle feasibility studies, but they have the potential to lead to a widely useful generic non-invasive molecular tool delivery platform for the brain. If successful, this delivery platform will reduce current barriers to testing newly developed tools for large-scale recording, manipulation, and imaging of neural activity, thereby dramatically increasing the capacity for efficient in vivo screening of a larger array of potential tools, thus enabling the neuroscience community to fully benefit from recent and ongoing developments. Moreover, such a delivery platform would ultimately be compatible with applications in humans.